1.
Introduction -
One of the principles of evidence-based
medicine is that concepts that fail
to withstand scientific scrutiny are
to be discarded. Such a time has come
for the belief that testosterone (T)
causes enhanced growth of prostate
cancer (pCA). This change in perspective
is prompted not only by current evidence,
but also by critical examination of
the historical origins of the belief.

In 1941
Huggins and Hodges [1] established the
hormonal responsiveness of pCA by reporting
that marked reductions in T by castration
or estrogen treatment caused metastatic
pCA to regress, and also that administration
of exogenous T caused pCA to grow. Many
of us learned from our professors to
describe the relationship of T to pCA
as “fuel for a fire” and “food
for a hungry tumor.” To this day,
androgen ablation remains a mainstay
of treatment for advanced pCA, and the
concern regarding T and the risk of pCA
has reached to the highest levels of
medicine.

In 2001
the then-director of the National Cancer
Institute in the United States explained
his reluctance to fund a large testosterone
replacement therapy (TRT) trial by stating
that he was “concerned that testosterone
could spur the growth of prostate cancer
among some men in the study” [2].
TRT has long been considered taboo among
men with a prior history of pCA regardless
of disease status, and product information
mandated by the US Food and Drug Administration
states that “known or suspected
carcinoma of the prostate” is a
contraindication for T products [3].
Three years ago the US National Institutes
of Health temporarily halted all T-related
research, in part on the basis of safety
concerns related to T and pCA, until
the Institute of Medicine pondered how
to best perform research in this area.

This
relationship of T to pCA has come under
greater scrutiny over the last decade
with the increased interest in the treatment
of hypogonadism with TRT, and the growing
number of pCA survivors who are symptomatically
hypogonadal and requesting treatment.
While there is no dispute that castration
causes pCA to regress, proof for the
second part of Huggins’ assertion,
that T causes pCA to grow, has been elusive.

Recent
reviews [4], [5], [6] have failed to
find any compelling evidence to support
this contention. The report by the Institute
of Medicine concluded, “In summary,
the influence of testosterone on prostate
carcinogenesis and other prostate outcomes
remains poorly defined…” [7].
The lack of evidence for what has been
assumed for decades to be a solid relationship
between T and pCA has been confusing
for clinicians and the public. As a student
once asked innocently, “If testosterone
is so bad for prostate cancer, why is
it so hard to prove?”

The underlying
logic has always been strained and inconsistent.
The disease is almost never seen during
the peak T years of the late teens and
early 20s, and only becomes prevalent
when men are older and T levels have
declined (Fig. 1). If T were really “fuel
for a fire,” then why would the
microfoci of pCA noted in young men from
autopsy studies [8] not develop into
frank cancer at early ages? If the answer
is that it may take 30 or 40 yr for T
to stimulate pCA to grow into a clinical
tumor, then why do we have any hesitation
in offering TRT to men in their 60s and
70s?

Fig.
1. Prostate cancer prevalence and testosterone
levels with ageing. pCA: prostate cancer,
T: testosterone.
In the absence of current supporting
evidence for the concept that T causes
enhanced pCA growth, an investigation
was performed of the early literature
on this topic to examine the historical
origins of this belief.

2. Huggins’ experiment
with T injections and pCA
In a 1967 review, Huggins [9] provided
this perspective on his landmark 1941
work: “Orchiectomy or the administration
of phenolic estrogens resulted in regression
of cancer of the human prostate whereas,
in untreated cases, testosterone enhanced
the rate of growth of the neoplasm.” What
does the paper actually show?

In addition
to showing that castration and estrogen
treatment caused acid phosphatase levels
to decline in men with metastatic pCA,
Huggins and Hodges [1] reported that
daily injection of testosterone propionate
caused acid phosphatase levels to increase.
Although three men were injected with
testosterone propionate, results were
only provided for two. One of these two
had already been castrated. In the remaining
individual, acid phosphatase levels rose
during 18 d of T injection, but fluctuated
widely before and afterwards, reaching
the same peak levels 3 wk after discontinuation
of T. No other clinical information was
offered.

The original assertion
that T caused pCA growth in untreated
individuals was thus based on equivocal
acid phosphatase results in a single
individual.

3. Additional
experience with exogenous T in men with
metastatic pCA
The largest series of exogenous T in
men with metastatic pCA was reported
by Fowler and Whitmore [10], who reviewed
the experience at Memorial Sloan Kettering
Cancer Center in New York from 1949 to
1967. Sixty-seven men, all with a history
of bone metastases, received T injections
under various protocols, and unfavorable
responses were noted, which included
subjective symptoms, such as increased
bone pain, or objective progression,
including a rise in acid phosphatase.
Of 52 men with evaluable responses, 45
had unfavorable responses. However, only
four of these men had not previously
undergone orchiectomy or estrogen treatment.
Within this untreated group one man had
an early “unfavorable response” (within
30 d of beginning T injections), another
had a subjective “beneficial response,” and
the remaining two eventually developed
unfavorable responses at 56 and 310 d
of daily T administration, respectively.
Given the advanced stage of pCA in these
men and the lack of a control group,
we must consider that the “unfavorable
responses” seen in this population
may have been due to the natural history
of their disease.

Largely
overlooked by history is the experience
of other investigators of that era, who
failed to note progression of pCA with
exogenous T and even noted beneficial
effects in some [11], [12]. For example,
Prout and Brewer [12] reported results
of daily T injections for a median of
13 d in 26 men with stage C and D disease,
of whom 20 had not undergone castration
or other hormonal treatment. “Most
of these individuals experienced an increase
in sense of well being and some noticed
vague diminution in pain.” In addition,
they reported that the acid phosphatase
response to T injection was “extremely
variable.”

Pearson
[13] reported on a previously untreated
patient with advanced prostatic cancer
with severe bone pain from osseous metastases,
who was treated with daily injections
of testosterone propionate. “There
was prompt relief of pain, and within
a few weeks he was asymptomatic.” The
patient remained asymptomatic for 9 mo,
during which time he received daily T
injections.

These
various historical reports lack modern
standards for determining true progression
of pCA, such as a reliable marker (i.e.,
prostate-specific antigen [PSA]) or control
groups. However, no studies within the
last 25 yr have replicated these early
experiences with T administration in
men with pCA. Despite their limitations,
these reports thus provide a valuable
perspective on the effect of T on pCA
progression. The failure to observe rapid
clinical progression with T administration
even in men with advanced disease argues
strongly against the contention that
T causes enhanced growth of pCA.

4. T
and pCA in the modern era
4.1. Testosterone flare
With the introduction in the 1980s of
luteinising hormone-releasing hormone
agonists that reduced T to castrate levels,
it was noted that a transient rise in
T occurred over the first 8–10
d. Reports of adverse events occurring
during this period of time, such as increased
bone pain, urinary retention, and vertebral
collapse with paraplegia, have been attributed
to pCA growth attributable to this “testosterone
flare” [14].
However, in the few studies that measured
PSA in men with advanced pCA during the
period of elevated testosterone, PSA
values never rose above baseline [15],
[16] Since PSA correlates well with pCA
progression [17], the flat PSA curve
noted during the interval of T flare
suggests that increased T did not cause
pCA to progress in these patients. Is
it possible that the adverse events noted
during the flare interval may have been
due to the natural history of metastatic
pCA or to the direct effects of T on
bone metabolism?

4.2.
Clinical trials of TRT
No large, long-term studies of TRT have
been performed. However, the pCA rate
in published TRT trials is approximately
1% [4]. This rate is similar to the cancer
detection rate in prostate cancer-screening
trials. Nevertheless, it must also be
recognized that the number of men included
in studies of =1 yr is quite small.

4.3.
Longitudinal studies
The relationship of T and other hormones
to subsequent development of pCA has
been studied in at least 16 population-based
longitudinal studies [18], [19], [20],
[21], [22]. Not one has shown a direct
correlation between total T levels and
pCA. Isolated associations with minor
androgens [23], calculated free T [19],
or quartile analysis of hormone ratios
[24] have not been confirmed by subsequent
studies [18], [20], [21], [22]. Surprisingly,
the largest study [20] of this type noted
an increased pCA risk with low T levels.

4.4.
pCA rates in men with low T
If high T is believed to be associated
with an increased risk of pCA, it follows
that low T should be associated with
reduced risk. However, prostate biopsy
in 77 hypogonadal men with normal digital
rectal examination and PSA of =4.0ng/ml
revealed cancer in 11 men [25]. This
14.3% cancer rate is similar to the 15.2%
pCA rate noted by Thompson et al. [26]
in the placebo arm of the Prostate Cancer
Prevention Trial.

4.5.
TRT in a high-risk population
Frank pCA has been reported to develop
over 3 years in =25% of men with high-grade
prostatic intraepithelial neoplasia (PIN)
[27]. In one study [28], TRT was provided
to 20 hypogonadal men with PIN and 55
hypogonadal men with benign biopsies.
At the end of 12 mo, pCA was identified
in one man in the PIN group and none
in the benign group, which represents
a 5% cancer rate in the PIN group and
a 1.3% risk overall. These results do
not suggest a precipitous increase of
pCA growth or development in this high-risk
group.

5. Resolving
the paradox
The paradox of these data can be summarized
as follows: Since lowering T causes pCA
to regress, why is it that raising T
fails to cause pCA to grow? The solution
lies in the concept of saturation, in
which maximal stimulation of pCA growth
is achieved at some relatively low concentration
of T. This model for T and pCA was suggested
by Fowler and Whitmore [10], who concluded
a quarter century ago that “normal
endogenous testosterone levels may be
sufficient to cause near maximal stimulation
of prostatic tumors.”

At T
levels below the saturation point, pCA
growth would be expected to vary with
T concentration, which is consistent
with the observation of pCA regrowth
with T normalization after androgen ablation.
This model is also supported by the observation
that exogenous T administered to normal
men fails to cause any increase in PSA
or prostate volume [29], [30]. In hypogonadal
men, TRT results in only modest increases
in prostate size, approximately 15% for
PSA and prostate volume [4], with volume
increasing to match eugonadal men, but
rising no higher [31].

6. Conclusions
The original assertion that higher T
causes enhanced pCA growth has persisted
as a medical myth since 1941 despite
all evidence to the contrary. Longitudinal
studies have repeatedly and consistently
rejected this hypothesis. And if T
is “food for a hungry tumor,” then
why is the cancer rate only 1% for
men receiving TRT when one of seven
hypogonadal men has biopsy-detectable
pCA?

Yet the true nature of
this myth is revealed best by its historical
origin—an equivocal blood test
result in a single patient. Other investigators
failed to note worrisome pCA progression
with T administration and even reported
beneficial subjective responses. Reviewing
the relatively benign clinical course
of their previously untreated patients,
Fowler and Whitmore [10] postulated that
near-maximal stimulation of pCA occurs
at T concentrations found in normal men.
This saturation model is consistent with
current data regarding T and pCA. In
summary, there is not today—nor
has there ever been—a scientific
basis for the contention that a higher
T concentration causes pCA growth, acutely
or long-term.

The danger
of belief trumping evidence is that it
impairs our ability to behave logically
and consistently, and can cause us to
disregard awkward data that may ultimately
provide promising avenues for research.
Can we continue to justify denying TRT
to symptomatic hypogonadal men after
definitive treatment for localized pCA
when history teaches us that T administration
failed to cause disease progression even
in men with untreated, widely metastatic
pCA? Might there also be clues regarding
the biology of pCA in the accumulating
evidence linking low T with pCA, including
associations with high-grade disease
[32], higher stage at presentation [33],
and worse prognosis [34]? Might it even
be possible that androgen administration
could prevent pCA [35], [36]? After 65
yr it is time to discard the myth and
to entertain new ideas regarding the
relationship of T and pCA.

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